To date at least 13 functional nonallelic human IFN-&#945; genes have been identified which produce 12 distinct proteins with more than 50 variants that exhibit a wide breadth and varied profile of biological activities (1, 31). Why so many IFN-&#945; species exist is still unknown and is a major question of our studies. The structures of human IFN-&#945; molecules consist of five &#945;-helices (labeled A-E, Figure 1), which are linked by an AB loop and three shorter segments. Human IFN-&#945;2c and IFN-&#945;21b are evolutionarily diverse forms of the IFN-&#945;s that exhibit unique receptor binding properties. Based on their secondary and tertiary structures, engineering constructs from these two IFNs offers the possibility of understanding more about the structure of human IFN-&#945;s and their relationships to antiviral, immunological, and antiproliferative/ programmed cell death activities. The primary, secondary, and tertiary structures of IFN-&#945; proteins are crucial for IFN-&#945; binding affinity and establishment of signal transduction pathways and biological activity. This work resulted in the production of eighteen novel IFN-&#945; molecular clones. From these, thirteen novel IFN-&#945; proteins have been expressed and characterized for their antiviral and antiproliferative properties. The optimization of IFN-&#945; protein expression is in progress.